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HIV-1 adaptation to NK-cell-mediated immune pressure.
Nature. 2011 Aug 4; 476(7358):96-100
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09 Aug 2011
New Finding
DOI: 10.3410/f.12533956.13761054
Escaping from killers: HIV-1 not only escapes cytotoxic T lymphocytes but also natural killer (NK) cells. Combining epidemiologic and functional studies, Marcus Altfeld's lab is able to show that mutations in HIV-1 are selected for enhanced binding of killer immunoglobulin-like receptors (KIRs) to Hinfected...Continue reading
Escaping from killers: HIV-1 not only escapes cytotoxic T lymphocytes but also natural killer (NK) cells. Combining epidemiologic and functional studies, Marcus Altfeld's lab is able to show that mutations in HIV-1 are selected for enhanced binding of killer immunoglobulin-like receptors (KIRs) to HIV-infected CD4+ T lymphocytes.
KIRs are a highly polymorphic family of receptors expressed by NK cells. The authors observe certain HIV polymorphisms only in HIV-1-infected individuals who are positive for the KIR2DL2 receptor. Previous studies revealed that peptides presented by human leukocyte antigen (HLA) class I molecules can positively or negatively influence binding to inhibitory KIRs. In this context, Altfeld and colleagues demonstrate that, in contrast to wildtype, the mutated HIV peptides strongly bind to KIR2DL2. Thereby, inhibitory signals are transmitted to KIR2DL2-expressing NK cells and infected cells escape NK-mediated killing. These data impressively demonstrate the importance of NK cells in HIV-1 infection.
KIRs are a highly polymorphic family of receptors expressed by NK cells. The authors observe certain HIV polymorphisms only in HIV-1-infected individuals who are positive for the KIR2DL2 receptor. Previous studies revealed that peptides presented by human leukocyte antigen (HLA) class I molecules can positively or negatively influence binding to inhibitory KIRs. In this context, Altfeld and colleagues demonstrate that, in contrast to wildtype, the mutated HIV peptides strongly bind to KIR2DL2. Thereby, inhibitory signals are transmitted to KIR2DL2-expressing NK cells and infected cells escape NK-mediated killing. These data impressively demonstrate the importance of NK cells in HIV-1 infection.
Disclosures
None declared
Add Comment
Walter L: F1000Prime Recommendation of [Alter G et al., Nature 2011, 476(7358):96-100]. In F1000Prime, 09 Aug 2011; DOI: 10.3410/f.12533956.13761054. F1000Prime.com/12533956#eval13761054
24 Aug 2011
Hanneke Schuitemaker
F1000 Infectious Diseases
Academic Medical Center, University of Amsterdam,
Amsterdam, Netherlands.
F1000 Infectious Diseases
Academic Medical Center, University of Amsterdam,
Amsterdam, Netherlands.
Neeltje Kootstra
F1000 Infectious Diseases
Academic Medical Center, University of Amsterdam,
Amsterdam, Netherlands.
F1000 Infectious Diseases
Academic Medical Center, University of Amsterdam,
Amsterdam, Netherlands.
New Finding
DOI: 10.3410/f.12533956.14149054
This is a very interesting paper that clearly demonstrates a role for natural killer (NK) cells in HIV-1 infection. Furthermore, Alter et al. show that HIV-1 is able to adapt and evade the antiviral activity of NK cells.
To test whether HIV-1 is able to evade recognition by NK cells through selection...Continue reading
To test whether HIV-1 is able to evade recognition by NK cells through selection...Continue reading
This is a very interesting paper that clearly demonstrates a role for natural killer (NK) cells in HIV-1 infection. Furthermore, Alter et al. show that HIV-1 is able to adapt and evade the antiviral activity of NK cells.
To test whether HIV-1 is able to evade recognition by NK cells through selection of escape mutations, Alter et al. performed a screen for sequence polymorphisms in HIV-1 that were associated with killer immunoglobulin-like receptor (KIR) genotypes. A total of 22 amino acid changes were identified to be associated with specific KIR genotypes. In depth analysis of three polymorphisms (in vpu/env, gag and nef) associated with the KIR2DL2 genotype revealed that the polymorphisms had no effect on viral replication but prevented activation of KIR2DL2+ NK cells. The KIR2DL2 receptor had a higher affinity for cells infected with virus that contains the polymorphism, thereby providing a stronger inhibitory signal to KIR2DL2+ NK cells and protecting infected cells from NK-mediated cell lysis. In this paper, it was clearly demonstrated that NK cells are able to control HIV-1 replication and that HIV-1 is able to escape from the NK cell-mediated antiviral activity.
To test whether HIV-1 is able to evade recognition by NK cells through selection of escape mutations, Alter et al. performed a screen for sequence polymorphisms in HIV-1 that were associated with killer immunoglobulin-like receptor (KIR) genotypes. A total of 22 amino acid changes were identified to be associated with specific KIR genotypes. In depth analysis of three polymorphisms (in vpu/env, gag and nef) associated with the KIR2DL2 genotype revealed that the polymorphisms had no effect on viral replication but prevented activation of KIR2DL2+ NK cells. The KIR2DL2 receptor had a higher affinity for cells infected with virus that contains the polymorphism, thereby providing a stronger inhibitory signal to KIR2DL2+ NK cells and protecting infected cells from NK-mediated cell lysis. In this paper, it was clearly demonstrated that NK cells are able to control HIV-1 replication and that HIV-1 is able to escape from the NK cell-mediated antiviral activity.
Disclosures
None declared
Schuitemaker H and Kootstra N: F1000Prime Recommendation of [Alter G et al., Nature 2011, 476(7358):96-100]. In F1000Prime, 24 Aug 2011; DOI: 10.3410/f.12533956.14149054. F1000Prime.com/12533956#eval14149054
12 Sep 2011
Barbara Rehermann
F1000 Microbiology
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health,
Bethesda, MD, USA.
F1000 Microbiology
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health,
Bethesda, MD, USA.
New Finding
DOI: 10.3410/f.12533956.14542221
This paper brings yet more discouraging news for HIV researchers. In this paper, Alter and colleagues provide convincing proof that HIV-1 begins to disarm the host immune response even earlier in the disease process than previously thought.
Using a data mining approach, the authors observed the clustering...Continue reading
Using a data mining approach, the authors observed the clustering...Continue reading
This paper brings yet more discouraging news for HIV researchers. In this paper, Alter and colleagues provide convincing proof that HIV-1 begins to disarm the host immune response even earlier in the disease process than previously thought.
Using a data mining approach, the authors observed the clustering of certain viral polymorphisms in HIV-1-infected individuals expressing the inhibitory killer immunoglobulin-like receptor (KIR)2DL2 on their natural killer (NK) cells. An in vitro experiment showed that KIR2DL2+ NK cells are unable to undergo robust activation and are incapable of controlling the replication of viral strains bearing these polymorphisms. Thus, these polymorphisms are thought to confer a survival advantage to the virus as they allow the virally infected cells to better bind the inhibitory KIR2DL2 receptor which, in turn, allows the virus to escape recognition and lysis by NK cells.
The findings of this paper suggest that the NK cells are important for both the host and virus response; not only do they lyse virally infected cells, they also exert a significant selection pressure which drives viral evolutionary dynamics and helps shape the population diversity of HIV-1.
It would be interesting to see if this phenomenon is mirrored in other chronic viral infections where the KIR genotype is known to have distinctive effects on infection outcome, such as in hepatitis C virus infection.
Using a data mining approach, the authors observed the clustering of certain viral polymorphisms in HIV-1-infected individuals expressing the inhibitory killer immunoglobulin-like receptor (KIR)2DL2 on their natural killer (NK) cells. An in vitro experiment showed that KIR2DL2+ NK cells are unable to undergo robust activation and are incapable of controlling the replication of viral strains bearing these polymorphisms. Thus, these polymorphisms are thought to confer a survival advantage to the virus as they allow the virally infected cells to better bind the inhibitory KIR2DL2 receptor which, in turn, allows the virus to escape recognition and lysis by NK cells.
The findings of this paper suggest that the NK cells are important for both the host and virus response; not only do they lyse virally infected cells, they also exert a significant selection pressure which drives viral evolutionary dynamics and helps shape the population diversity of HIV-1.
It would be interesting to see if this phenomenon is mirrored in other chronic viral infections where the KIR genotype is known to have distinctive effects on infection outcome, such as in hepatitis C virus infection.
Disclosures
None declared
Rehermann B and Raghuraman S: F1000Prime Recommendation of [Alter G et al., Nature 2011, 476(7358):96-100]. In F1000Prime, 12 Sep 2011; DOI: 10.3410/f.12533956.14542221. F1000Prime.com/12533956#eval14542221
26 Sep 2011
Controversial
DOI: 10.3410/f.12533956.14653197
Alter and colleagues propose that a variant Vpu peptide binding to HLA-C inhibits natural killer (NK) cell killing of HIV-infected cells in individuals with the inhibitory KIR2DL2 receptor - suggesting killer immunoglobulin-like receptor (KIR)-dependent selection for this HIV variant. Although an interesting...Continue reading
Alter and colleagues propose that a variant Vpu peptide binding to HLA-C inhibits natural killer (NK) cell killing of HIV-infected cells in individuals with the inhibitory KIR2DL2 receptor - suggesting killer immunoglobulin-like receptor (KIR)-dependent selection for this HIV variant. Although an interesting concept, it is difficult to understand how a few new variant Vpu peptides, in a sea of host self-peptides bound to HLA-C on the cell surface that already serve as inhibitory ligands for KIR2DL2, can substantially increase the inhibition of NK cell-mediated killing of infected cells. Furthermore, the 'group 1' HLA-C alleles that function as ligands for KIR2DL2 comprise a few hundred different allelic variants that likely vary considerably in their peptide specificity.
It is easy to understand how an activating receptor, such as the T cell receptor, can stimulate the response of an immune cell even if very few peptide-MHC complexes are present on a virus-infected cell. But it is unexplained how a few variant viral peptides - in competition with an abundance of host self-peptides - could substantially increase signals through an inhibitory KIR.
It is easy to understand how an activating receptor, such as the T cell receptor, can stimulate the response of an immune cell even if very few peptide-MHC complexes are present on a virus-infected cell. But it is unexplained how a few variant viral peptides - in competition with an abundance of host self-peptides - could substantially increase signals through an inhibitory KIR.
Disclosures
None declared
Lanier L: F1000Prime Recommendation of [Alter G et al., Nature 2011, 476(7358):96-100]. In F1000Prime, 26 Sep 2011; DOI: 10.3410/f.12533956.14653197. F1000Prime.com/12533956#eval14653197
F1000Prime Recommendations, Dissents and Comments for [Alter G et al., Nature 2011, 476(7358):96-100]. In F1000Prime, 26 May 2013; F1000Prime.com/12533956
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Natural killer (NK) cells have an important role in the control of viral infections, recognizing virally infected cells through a variety of activating and inhibitory receptors. Epidemiological and functional studies have recently suggested that NK cells can also contribute to the control of HIV-1 infection through recognition of virally infected cells by both activating and inhibitory killer immunoglobulin-like receptors (KIRs). However, it remains unknown whether NK cells can directly mediate antiviral immune pressure in vivo in humans. Here we describe KIR-associated amino-acid polymorphisms in the HIV-1 sequence of chronically infected individuals, on a population level. We show that these KIR-associated HIV-1 sequence polymorphisms can enhance the binding of inhibitory KIRs to HIV-1-infected CD4(+) T cells, and reduce the antiviral activity of KIR-positive NK cells. These data demonstrate that KIR-positive NK cells can place immunological pressure on HIV-1, and that the virus can evade such NK-cell-mediated immune pressure by selecting for sequence polymorphisms, as was previously described for virus-specific T cells and neutralizing antibodies. NK cells might therefore have a previously underappreciated role in contributing to viral evolution.
DOI: 10.1038/nature10237
PMID: 21814282
